CerRx, Inc., Lubbock TX, a clinical stage anticancer drug development start-up company, requests critical funding via this SBIR Fast-Track Phase I/II application to support a highly novel, adult Phase I clinical trial of intravenous fenretinide + safingol, for which it licenses both formulation and drug combination IP rights. This trial will be subcontracted to the academic West Texas-based, South Plains Oncology Consortium (SPOC), based at the Texas Tech University Health Sciences Center (TTUHSC). Fenretinide (4-HPR) is a p53- independent retinoid selectively cytotoxic to cancer cells via increase of reactive oxygen species and the de novo increase of native long chain D-erythro-dihydroceramides. Safingol is L-threo-dihydrosphingosine, an artificial stereochemical variant of sphinganine, the native precursor of dihydroceramides in mammalian cells. We have shown in human and canine cancer cell lines that safingol is incorporated into long-lived, L-threodihydroceramides. Our preclinical data demonstrated that safingol strikingly synergized fenretinide cytotoxicity in vitro by simultaneously increasing both artificial L-threo-dihydroceramides and native D-erythrodihydroceramides in a tumor cell-specific manner. We hypothesized that this novel, cancer-specific biochemistry might be achievable in human cancers should adequate drug levels be achievable in patient tumors in situ. Via an NCI RAID grant, novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery were developed. Phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced multiple durable complete responses in relapsed T-cell lymphomas with additional signals of activity in solid tumors. A Phase I trial of our intravenous safingol formulation demonstrated that it was well-tolerated in combination with cisplatin at safingol doses predicted sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol + fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. Under SBIR Phase I, initial proof-of-concept clinical combination dosing will be conducted. Under SBIR Phase II, a Phase I dose escalation trial of intravenous 4- HPR + safingol in adult solid tumors and lymphomas will be conducted. The Phase I trial will define the maximally tolerated dose (MTD) of intravenous safingol when combined with fenretinide, the pharmacokinetics of both agents in combination, obtain ancillary markers of the pharmacodynamic actions of both agents in combination by measuring plasma sphingolipid and sphingosine-1-phosphate levels, and, within the confines of a phase I trial, determine the activity of this novel drug combination. This trial is the first in man to specifically target the dihydroceramide pathway as a cytotoxic cancer treatment. If successful, this novel biochemistry may constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies.